US4083987A - 4-Imino-1,3-diazabicyclo-(3.1.0)-hexan-2-one as a cancerostat and immuno-stimulant - Google Patents
4-Imino-1,3-diazabicyclo-(3.1.0)-hexan-2-one as a cancerostat and immuno-stimulant Download PDFInfo
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- US4083987A US4083987A US05/690,340 US69034076A US4083987A US 4083987 A US4083987 A US 4083987A US 69034076 A US69034076 A US 69034076A US 4083987 A US4083987 A US 4083987A
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- hexan
- imino
- diazabicyclo
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- stimulant
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
Definitions
- the present invention is concerned with a new substance which is cancerostatic and has an immunity-stimulating action and is also concerned with the preparation thereof.
- 1-carboxamido-2-cyanoaziridine which is described in German Democratic Republic Pat. No. 110,492
- a substantially anhydrous, polar, organic solvent preferably in an alcohol containing up to 4 carbon atoms
- a catalytic amount of an alkali to give the above new compound, which crystallizes readily, is stable in dry form and is very readily soluble in water, physiological saline and aqueous alkali metal hydroxide solutions.
- the structure of the new compound has not been finally elucidated but the physico-chemical investigations (analysis, mass spectrum, infra-red spectrum and NMR spectrum) which have been carried out with the compound indicate one of the above structures (I), (II) or (III).
- the good water solubility, as well as the decomposition point of the substance of over 250° C. indicate ionic exchange actions and thus also the above-described tautomeric structures.
- the infra-red spectrum of the compound in potassium bromide shows two wide bands between 3300 to 2500 cm -1 and 1800 to 1400 cm -1 , sharper bands, for example, at 1295 cm -1 , 1232 cm -1 , 1178 cm -1 , 1013 cm -1 , 922 cm -1 , 855 cm -1 , 820 cm -1 , 682 cm -1 and 542 cm -1 .
- the mass spectrum shows a mol peak at 111, as well as peaks at 110, 83, 68 and 41.
- the following Table shows that the tumor growth is significantly inhibited in the case of intravenous and oral administration of the substance.
- the active material dissolved in 5 ml physiological saline, was administered intravenously into a vein in the tails of 8 Sprague-Dawley rats with an average body weight of 200 to 250 g.
- 1 to 2 drops of blood were taken from a tail vein and the corpuscular blood components determined. The average values were determined statistically from the 8 values of the individual animals.
- mice 20 male white mice with a body weight of 20 to 25 g were each immunized with 1 ml preserved sheep erythrocytes (1 ml contains 5 ⁇ 10 8 erythrocytes).
- 4-imino-1,3-diazabicyclo[3.1.0]hexan-2-one or a comparative active material dissolved in 5 ml physiological saline/kg. mouse body weight, were administered intravenously.
- 20 animals were also immunized with 1 ml sheep erythrocytes and treated with 5 ml/kg physiological saline.
- the spleens of the animals were removed under sterile conditions and the number of antibody-forming spleen cells determined according to Jerne's technique. The individual values were determined. The individual results are summarized in the following Table 3:
- the acute toxicity (LD 50 ) in the case of a single intravenous dose was ascertained to be 660 mg/kg in the case of rats and 750 mg/kg in the case of mice.
- the LD 50 in the case of oral administration was found to be more than 4.0 mg/kg in the case of mice.
- the present invention also provides pharmaceutical composition
- pharmaceutical composition comprising the new compound and/or at least one physiologically compatible salt thereof, in admixture with a solid or liquid pharmaceutical diluent or carrier.
- compositions 4-imino-1,3-diazabicyclo[3.1.0]hexan-2-one and/or at least one pharmacologically compatible salt thereof is mixed in known manner with an appropriate pharmaceutical carrier substance and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or an oil, for example olive oil, and placed in capsules.
- the active material is acid labile
- the composition is provided with a coating which only dissolves in the alkaline medium of the intestines or an appropriate carrier material, for example a high molecular weight fatty acid or carboxymethyl-cellulose is mixed therewith.
- solid carrier materials include starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (for example stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols).
- Compositions suitable for oral administration can, if desired, contain flavoring and/or sweetening materials.
- the active material is preferably injected.
- injection medium it is preferred to use water which contains the additives usual in the case of injection solutions, such as stabilizing agents, solubilizing agents and/or weakly alkaline buffers.
- Additives of this type include, for example, phosphate and carbonate buffers, ethanol, complex-forming agents (for example ethylenediamine-tetraacetic acid and the non-toxic salts thereof) and high molecular weight polymers (for example liquid polyethylene oxide) for viscosity regulation.
- any physiologically compatible anion can be used, e.g. acetate, citrate, lactate, chloride, bromide, sulfate, phosphate, sulfonates, and the like.
- These salts can be made by mixing the active compound with aqueous acid.
- polar solvents other than methanol can be employed in amount sufficient to dissolved the starting material and end product, e.g. other lower alkanols, dioxane, dimethylsulfoxide, dimethylformamide. Heat is desirable to speed up the isomerization.
- potassium hydroxide there can be used other soluble alkalis, e.g. hydroxides and/or carbonates of sodium, lithium, and even strong quaternary ammonium bases.
- the basic catalyst can be used in as little as about 1 mole % but about 10 mole % is suitable and more can be used, although not necessary.
- the active material may be applied one or more times with each dose containing about 25 to 3000 and preferably about 50 to 500 mg of active material.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
4-Imino-1,3-diazabicyclo[3.1.0]-hexan-2-one of one or more of the tautomeric formulas ##STR1## or a physiologically compatible salt thereof exhibits cancerostatic and immuno-stimulant activity. It is produced by cyclized 1-carboxamido-2-cyanoaziridine in an anhydrous polar organic solvent in the presence of a catalytic amount of an alkali.
Description
The present invention is concerned with a new substance which is cancerostatic and has an immunity-stimulating action and is also concerned with the preparation thereof.
A number of cancerostatically-acting substances is already known which, by means of their attack in the metabolism of the very rapidly dividing cancer cells, so strongly damage the tumors that the growth thereof is reduced or even a regression is achieved. However, a complete regression only by medication is very difficult to achieve since, in the case of the necessarily high dosages, healthy body tissues are also attacked and destroyed. On the other hand, it has been found that most cytostatic compounds, at the necessarily high dosages, damage the body's inherent immune defense mechanism so that this is no longer able to destroy the remaining cancer cells or to prevent a further growth thereof. In addition, due to the reduction of the immune defense mechanism, the susceptibility of the already weakened body to bacterial or viral infections is increased.
Consequently, there is a great need for a cancerostatically-effective therapeutic substance which does not impair the body's inherent immune mechanism or which stimulates it.
We have now found that 4-imino-1,3-diazabicyclo-[3.1.0]hexan-2-one and the physiologically compatible salts thereof possess the desired cancerostatic and immunity-stimulating properties. This compound can be represented by the following tautomeric structural formulae: ##STR2##
However, it is not certain whether the compound itself or a metabolite thereof formed in the body represents the actual active principle.
We have found that 1-carboxamido-2-cyanoaziridine, which is described in German Democratic Republic Pat. No. 110,492, can be cyclized in a substantially anhydrous, polar, organic solvent, preferably in an alcohol containing up to 4 carbon atoms, with the addition of a catalytic amount of an alkali to give the above new compound, which crystallizes readily, is stable in dry form and is very readily soluble in water, physiological saline and aqueous alkali metal hydroxide solutions.
The structure of the new compound has not been finally elucidated but the physico-chemical investigations (analysis, mass spectrum, infra-red spectrum and NMR spectrum) which have been carried out with the compound indicate one of the above structures (I), (II) or (III). The good water solubility, as well as the decomposition point of the substance of over 250° C. indicate ionic exchange actions and thus also the above-described tautomeric structures.
The following Example illustrates the preparation of the new compound according to the present invention:-
1.1 g (10 mMol) 1-carboxamido-2-cyanoaziridino is dissolved in 5 ml anhydrous methanol. 56 mg (1 mMol) potassium hydroxide in 5 ml anhydrous methanol are added dropwise at 50° C with the exclusion of moisture. Within the course of a few minutes, 0.66 g (6 mMol) 4-imino-1,3-diazabicyclo[3.1.0]hexan-2-one precipitate out, corresponding to a yield of 60% theory. After recrystallization from anhydrous methanol, the compound has a decomposition point of more than 250° C.
The infra-red spectrum of the compound in potassium bromide shows two wide bands between 3300 to 2500 cm-1 and 1800 to 1400 cm-1, sharper bands, for example, at 1295 cm-1, 1232 cm-1, 1178 cm-1, 1013 cm-1, 922 cm-1, 855 cm-1, 820 cm-1, 682 cm-1 and 542 cm-1.
The mass spectrum shows a mol peak at 111, as well as peaks at 110, 83, 68 and 41.
The NMR spectrum (deuterodimethyl formamide) shows the following bands;
______________________________________
chemical displacement
coupling constants
against TMS in ppm
in H.sub.2
______________________________________
V (1) = 2.23 J (1.2) 0.5
V (2) = 2.51 J (1.3) 2.93
V (3) = 3.47 J (2.3) 5.27
______________________________________
Microelementary analysis gives the following values:
______________________________________ C.sub.4 H.sub.5 ON.sub.3 calc. : C 43.24%; H 4.53%; N 37.82% found : 42.62%; 4.03%; 37.52% ______________________________________
The pharmacological properties of the new compound were determined as follows:
1. Cancerostatic Effectiveness
Sprague-Dawley rats with a body weight of 80 to 120 g and an age of 6 to 8 weeks were subcutaneously inoculated in the neck with tumor cells. In each case, there was used 0.1 ml of an aqueous suspension of about 106 tumor cells of the Walker sarcoma 256 (solid, rat).
4-Imino-1,3-diazabicyclo[3.1.0]hexan-2-one was dissolved in physiological saline solution (in each case, the desired amount in 5 ml solution/kg body weight of experimental animal). 6 Hours after inoculation of the animals, these solutions were administered intravenously or orally by means of a stomach tube. The control animals received 5 ml/kg body weight of physiological saline. 20 experimental animals and 20 control animals were used per experiment. The animals were sacrificed with ether after 10 days, the tumors extirpated and the weight of the tumors of the control group compared with those of the experimental group.
The following Table shows that the tumor growth is significantly inhibited in the case of intravenous and oral administration of the substance.
TABLE 1
______________________________________
Inhibition of the growth of Walker sarcoma 256 after a
single administraton of 4-imino-1,3-diazabicyclo[3.1.0]-
hexan-2-one to Sprague-Dawley rats
administration
amount
route mg./kg. % inhibition
______________________________________
intravenous 0.1 7.5
1.0 17.5
10.0 49.5
100.0 31.0
200.0 39.5
oral 5.0 20.0
125.0 62.0
______________________________________
2. Immunity-stimulating Action
The active material, dissolved in 5 ml physiological saline, was administered intravenously into a vein in the tails of 8 Sprague-Dawley rats with an average body weight of 200 to 250 g. As controls, there were used 8 rats which were only treated with 5 ml physiological saline per kg. body weight. In the following days, 1 to 2 drops of blood were taken from a tail vein and the corpuscular blood components determined. The average values were determined statistically from the 8 values of the individual animals.
It was found that the number of leukocytes increased considerably and also that the percentage proportion of the lymphocytes increased. Only after the expiry of 20 to 25 days were the values of the control animals again reached. On the other hand, the number of erythrocytes did not change significantly over the whole of the experimental period. The experimental results of the third day, which correspond approximately to the maximum increase, are summarized in the following Table 2:
TABLE 2
______________________________________
Increase of the leukocytes after a single intravenous
administration of 4-imino-1,3-diazobicyclo[3.1.0]hexan-
2-one to Sprague-Dawley rats on the third day after
administration
mg. active material/kg. rat
number of leukocytes/mm.sup.3
______________________________________
0 7,300
2 10,300
5 9,800
10 10,800
20 12,300
40 10,800
75 11,800
150 8,000
400 6,500
______________________________________
Furthermore, the number of antibody-forming spleen cells was determined by Jerne's method (Jerne et al., Science, 140, 405/1963).
20 male white mice with a body weight of 20 to 25 g were each immunized with 1 ml preserved sheep erythrocytes (1 ml contains 5 × 108 erythrocytes). On the same day, 4-imino-1,3-diazabicyclo[3.1.0]hexan-2-one or a comparative active material, dissolved in 5 ml physiological saline/kg. mouse body weight, were administered intravenously. For control purposes, 20 animals were also immunized with 1 ml sheep erythrocytes and treated with 5 ml/kg physiological saline. Three days after administration, the spleens of the animals were removed under sterile conditions and the number of antibody-forming spleen cells determined according to Jerne's technique. The individual values were determined. The individual results are summarized in the following Table 3:
TABLE 3
______________________________________
Average values of the antibody-forming spleen cells after
intravenous administration of various active materials
amount number of % of the
active material
mg/kg spleen cells
control
______________________________________
control -- 4,600 100
4-imino-1,3-diazabicyclo
[3.1.0]hexan- 2.5 23,000 500
2-one
phytohaemagglutinin
500.0 1,400 30
cyclophosphamide
125.0 460 10
______________________________________
From the above experiments, it can be deduced that for the desired pharmacological effect of immunity stimulation, a dosage of about 1 to 50 mg/kg body weight is necessary, which can be administered either all at once or in several individual doses. Since the effect slowly decreases after about 2 weeks, a further treatment can possibly be necessary.
The acute toxicity (LD50) in the case of a single intravenous dose was ascertained to be 660 mg/kg in the case of rats and 750 mg/kg in the case of mice. The LD50 in the case of oral administration was found to be more than 4.0 mg/kg in the case of mice.
The present invention also provides pharmaceutical composition comprising the new compound and/or at least one physiologically compatible salt thereof, in admixture with a solid or liquid pharmaceutical diluent or carrier.
For the preparation of pharmaceutical compositions, 4-imino-1,3-diazabicyclo[3.1.0]hexan-2-one and/or at least one pharmacologically compatible salt thereof is mixed in known manner with an appropriate pharmaceutical carrier substance and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or an oil, for example olive oil, and placed in capsules. Since the active material is acid labile, the composition is provided with a coating which only dissolves in the alkaline medium of the intestines or an appropriate carrier material, for example a high molecular weight fatty acid or carboxymethyl-cellulose is mixed therewith. Examples of solid carrier materials include starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (for example stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Compositions suitable for oral administration can, if desired, contain flavoring and/or sweetening materials.
However, the active material is preferably injected. As injection medium, it is preferred to use water which contains the additives usual in the case of injection solutions, such as stabilizing agents, solubilizing agents and/or weakly alkaline buffers. Additives of this type include, for example, phosphate and carbonate buffers, ethanol, complex-forming agents (for example ethylenediamine-tetraacetic acid and the non-toxic salts thereof) and high molecular weight polymers (for example liquid polyethylene oxide) for viscosity regulation.
When administered in the form of a salt, any physiologically compatible anion can be used, e.g. acetate, citrate, lactate, chloride, bromide, sulfate, phosphate, sulfonates, and the like. These salts can be made by mixing the active compound with aqueous acid.
In the preparation of the active material polar solvents other than methanol can be employed in amount sufficient to dissolved the starting material and end product, e.g. other lower alkanols, dioxane, dimethylsulfoxide, dimethylformamide. Heat is desirable to speed up the isomerization. In place of potassium hydroxide, there can be used other soluble alkalis, e.g. hydroxides and/or carbonates of sodium, lithium, and even strong quaternary ammonium bases. The basic catalyst can be used in as little as about 1 mole % but about 10 mole % is suitable and more can be used, although not necessary.
For treatment of humans the active material may be applied one or more times with each dose containing about 25 to 3000 and preferably about 50 to 500 mg of active material.
It will be appreciated that the instant specification and examples are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention.
Claims (7)
1. 4-Imino-1,3-diazabicyclo[3.1.0]-hexan-2-one or a physiologically compatible salt thereof.
2. A process for the preparation of 4-imino-1,3-diazabicyclo-[3.1.0]-hexan-2-one according to claim 1, comprising contacting 1-carboxamido-2-cyanoaziridine with a catalytic amount of an alkali in a substantially anhydrous polar solvent, whereby the aziridine cyclizes.
3. The process according to claim 2, wherein the solvent used is an anhydrous alcohol containing up to 4 carbon atoms.
4. The process according to claim 3, wherein the alkali is potassium hydroxide and the solvent is heated.
5. An immuno-stimulant composition containing an immuno-stimulant effective amount of 4-imino-1,3-diazabicyclo[3.1.0]-hexan-2-one or a physiologically compatible salt thereof according to claim 1 in admixture with a physiologically compatible diluent.
6. A unit dose of a composition according to claim 5 containing about 25 to 3000 mg of active material.
7. A method of stimulating an immune response in a patient which comprises administering to the patient an immuno-stimulant effective amount of 4-imino-1,3-diazabicyclo[3.1.0]-hexan-2-one or a physiologically compatible salt thereof according to claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DT2530398 | 1975-07-08 | ||
| DE19752530398 DE2530398A1 (en) | 1975-07-08 | 1975-07-08 | ORGANIC CONNECTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4083987A true US4083987A (en) | 1978-04-11 |
Family
ID=5950951
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US05/690,340 Expired - Lifetime US4083987A (en) | 1975-07-08 | 1976-05-26 | 4-Imino-1,3-diazabicyclo-(3.1.0)-hexan-2-one as a cancerostat and immuno-stimulant |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US4083987A (en) |
| JP (1) | JPS5210290A (en) |
| AR (1) | AR208802A1 (en) |
| AT (1) | AT345846B (en) |
| AU (1) | AU497292B2 (en) |
| BE (1) | BE843803A (en) |
| CA (1) | CA1069125A (en) |
| CH (1) | CH598259A5 (en) |
| CS (1) | CS198195B2 (en) |
| DD (1) | DD125079A5 (en) |
| DE (1) | DE2530398A1 (en) |
| DK (1) | DK139752C (en) |
| ES (1) | ES449597A1 (en) |
| FI (1) | FI59250C (en) |
| FR (1) | FR2316945A1 (en) |
| GB (1) | GB1490486A (en) |
| HU (1) | HU170252B (en) |
| IL (1) | IL49964A (en) |
| IN (1) | IN146367B (en) |
| LU (1) | LU75314A1 (en) |
| NL (1) | NL160564C (en) |
| PL (1) | PL98937B1 (en) |
| PT (1) | PT65327B (en) |
| SE (1) | SE409864B (en) |
| SU (1) | SU604482A3 (en) |
| ZA (1) | ZA763977B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3825667A1 (en) * | 1988-07-28 | 1990-03-15 | Boehringer Mannheim Gmbh | USE OF IMEXON AS IMMUNOSUPPRESSIVE |
| DE3844655A1 (en) * | 1988-07-28 | 1990-05-17 | Boehringer Mannheim Gmbh | Use of imexon as immunosuppressant |
| US4996219A (en) * | 1988-12-13 | 1991-02-26 | Boehringer Mannheim Gmbh | Imidazolidine derivatives as immunosuppressives |
| US5369119A (en) * | 1988-07-28 | 1994-11-29 | Boehringer Mannheim Gmbh | Use of imexon as an immune suppressive and pharmaceutical compositions containing imexon |
| WO2002041871A2 (en) * | 2000-11-21 | 2002-05-30 | Board Of Regents, The University Of Texas System | Composition comprising an imexon or derivatives thereof and lipids |
| US6476236B1 (en) | 2001-11-26 | 2002-11-05 | The Arizona Board Of Regents | Synthesis of 2-cyanoaziridine-1-carboxamide |
| US20030129222A1 (en) * | 2000-11-21 | 2003-07-10 | Gabriel Lopez-Berestein | Liposomal imexon |
| WO2006042662A1 (en) * | 2004-10-15 | 2006-04-27 | Heidelberg Pharma Gmbh | Parenteral forms of administration of imexon and method for the production thereof |
| WO2008045998A2 (en) * | 2006-10-12 | 2008-04-17 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Enantiomerically enriched iminopyrrolidone aziridine compositions |
-
1975
- 1975-07-08 DE DE19752530398 patent/DE2530398A1/en not_active Withdrawn
-
1976
- 1976-05-26 US US05/690,340 patent/US4083987A/en not_active Expired - Lifetime
- 1976-06-28 CA CA255,790A patent/CA1069125A/en not_active Expired
- 1976-06-29 DD DD193619A patent/DD125079A5/xx unknown
- 1976-07-01 DK DK297176A patent/DK139752C/en active
- 1976-07-02 AR AR263845A patent/AR208802A1/en active
- 1976-07-02 IL IL49964A patent/IL49964A/en unknown
- 1976-07-02 GB GB27657/76A patent/GB1490486A/en not_active Expired
- 1976-07-05 SE SE7607675A patent/SE409864B/en unknown
- 1976-07-05 HU HUBO1622A patent/HU170252B/hu unknown
- 1976-07-05 FI FI761958A patent/FI59250C/en not_active IP Right Cessation
- 1976-07-05 ZA ZA763977A patent/ZA763977B/en unknown
- 1976-07-05 AU AU15596/76A patent/AU497292B2/en not_active Expired
- 1976-07-05 BE BE168650A patent/BE843803A/en unknown
- 1976-07-05 CS CS764432A patent/CS198195B2/en unknown
- 1976-07-05 CH CH859076A patent/CH598259A5/xx not_active IP Right Cessation
- 1976-07-06 ES ES449597A patent/ES449597A1/en not_active Expired
- 1976-07-06 AT AT493176A patent/AT345846B/en not_active IP Right Cessation
- 1976-07-06 LU LU75314A patent/LU75314A1/xx unknown
- 1976-07-06 NL NL7607429.A patent/NL160564C/en not_active IP Right Cessation
- 1976-07-07 FR FR7620739A patent/FR2316945A1/en active Granted
- 1976-07-07 PL PL1976190969A patent/PL98937B1/en unknown
- 1976-07-07 PT PT65327A patent/PT65327B/en unknown
- 1976-07-08 JP JP51081456A patent/JPS5210290A/en active Granted
- 1976-07-08 SU SU762379563A patent/SU604482A3/en active
-
1977
- 1977-07-01 IN IN992/CAL/77A patent/IN146367B/en unknown
Non-Patent Citations (1)
| Title |
|---|
| hillers et al. Chem. Abst. 1972, vol. 76, No. 126,824j. * |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3825667A1 (en) * | 1988-07-28 | 1990-03-15 | Boehringer Mannheim Gmbh | USE OF IMEXON AS IMMUNOSUPPRESSIVE |
| DE3844655A1 (en) * | 1988-07-28 | 1990-05-17 | Boehringer Mannheim Gmbh | Use of imexon as immunosuppressant |
| US5369119A (en) * | 1988-07-28 | 1994-11-29 | Boehringer Mannheim Gmbh | Use of imexon as an immune suppressive and pharmaceutical compositions containing imexon |
| US4996219A (en) * | 1988-12-13 | 1991-02-26 | Boehringer Mannheim Gmbh | Imidazolidine derivatives as immunosuppressives |
| WO2002041871A3 (en) * | 2000-11-21 | 2003-04-17 | Univ Texas | Composition comprising an imexon or derivatives thereof and lipids |
| WO2002041871A2 (en) * | 2000-11-21 | 2002-05-30 | Board Of Regents, The University Of Texas System | Composition comprising an imexon or derivatives thereof and lipids |
| US20030129222A1 (en) * | 2000-11-21 | 2003-07-10 | Gabriel Lopez-Berestein | Liposomal imexon |
| US6476236B1 (en) | 2001-11-26 | 2002-11-05 | The Arizona Board Of Regents | Synthesis of 2-cyanoaziridine-1-carboxamide |
| EP1461316A2 (en) * | 2001-11-26 | 2004-09-29 | The Arizona Board of Regents | Synthesis of 2-cyanoziridine-1-carboxamide |
| EP1461316A4 (en) * | 2001-11-26 | 2005-04-27 | Univ Arizona | Synthesis of 2-cyanoziridine-1-carboxamide |
| WO2006042662A1 (en) * | 2004-10-15 | 2006-04-27 | Heidelberg Pharma Gmbh | Parenteral forms of administration of imexon and method for the production thereof |
| US20080096947A1 (en) * | 2004-10-15 | 2008-04-24 | Heidelberg Pharma Ag | Parenteral Forms Of Administration Of Imexon And Method For The Production Thereof |
| WO2008045998A2 (en) * | 2006-10-12 | 2008-04-17 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Enantiomerically enriched iminopyrrolidone aziridine compositions |
| WO2008045998A3 (en) * | 2006-10-12 | 2008-09-18 | Univ Arizona | Enantiomerically enriched iminopyrrolidone aziridine compositions |
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